Decoding human bone marrow hematopoietic stem and progenitor cells from fetal to birth

Area of Science:

• Developmental Biology
• Hematology
• Cancer Biology

Background:

• Bone marrow (BM) is the primary site of hematopoiesis post-20 weeks post-conception (PCW).
• The developmental trajectory of fetal BM hematopoiesis and its relation to malignancies are not fully understood.

Purpose of the Study:

• To investigate the single-cell transcriptomic profiles of fetal BM hematopoietic stem and progenitor cells (HSPCs).
• To elucidate the developmental dynamics of hematopoiesis in fetal BM from the early second trimester to the neonatal stage.
• To identify potential links between fetal hematopoiesis and leukemogenesis.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was employed to analyze BM HSPCs.
• Samples were collected at three distinct developmental stages: early second trimester (12-14 PCW), mid-second trimester (19-22 PCW), and neonatal stage.

Main Results:

• Hematopoietic stem cell and multipotent progenitor (HSC/MPP) stemness is established by the mid-second trimester and maintained until birth.
• Enhanced differentiation potential towards three major lineages and increased aerobic metabolism were observed post-mid-second trimester.
• Early second trimester HSPCs exhibited decreased stemness and elevated interferon signals, correlating with a higher susceptibility to leukemogenesis.

Conclusions:

• Fetal hematopoiesis undergoes significant dynamic changes in preparation for birth, establishing stemness and differentiation capacity.
• Specific molecular signatures in early fetal HSPCs may predispose individuals to leukemia.
• This study provides crucial insights into normal fetal hematopoietic development and its implications for understanding leukemia pathogenesis.